Published Online
on December 12, 2002

A more recent version of this article appeared on January 1, 2003

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Submitted on July 31, 2002
Accepted on August 20, 2002

Ischemic Preconditioning in the Hippocampus of a Knockout Mouse Lacking SUR1-Based K_ATP Channels

Alvaro Muñoz PhD; Mitsuhiro Nakazaki MD, PhD; J. Clay Goodman MD; Roberto Barrios MD; Carlos G. Onetti PhD; Joseph Bryan PhD; and Lydia Aguilar-Bryan MD, PhD^*

From the Departments of Medicine (A.M., L.A-B.), Molecular and Cellular Biology (M.N., J.B.), Neurosurgery (J.C.G.), and Pathology (J.C.G., R.B.), Baylor College of Medicine, Houston, Tex; First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan (M.N., J.B.); and Centro de Investigaciones Biomedicas, Universidad de Colima, Colima, Mexico (A.M., C.G.O.).

^* To whom correspondence should be addressed. E-mail: jbryan{at}bcm.tmc.edu.

Background and Purpose—ATP-sensitive K⁺ (K_ATP) channels have been implicated in the mechanism of neuronal ischemic preconditioning. To evaluate the role of neuronal/-cell-type K_ATP channels, SUR1 null (Sur1KO) mice lacking (K_IR6.x/SUR1)₄ K_ATP channels were subjected to a preconditioning protocol with the use of double carotid occlusion.

Methods—Wild-type C57BL/6 and Sur1KO mice were subjected to a double carotid block for 40 minutes with or without a 20-minute preconditioning block. After a 10-day reperfusion period, damage was assessed histologically in the hippocampal CA1, CA2, and CA3 areas and in the dentate gyrus. The neuroprotective effects of intracerebroventricular injections of diazoxide, which selectively affects mitochondria versus opening SUR1-type K_ATP channels, and 5-hydroxydecanoate, a selective blocker of mitoK_ATP channels, were evaluated with the same protocol.

Results—Neurons in the CA1 region of both Sur1KO and wild-type animals subjected to a 20-minute ischemic insult were protected equally from neuronal damage produced by a subsequent 40-minute ischemic period. Pretreatment with diazoxide protected both Sur1KO and wild-type neurons, while 5-hydroxydecanoate augmented neurodegeneration in both strains of animals when administered before a 20-minute bout of ischemia.

Conclusions—SUR1-based K_ATP channels are not obligatory for neuronal preconditioning or augmentation of neurodegeneration by 5-hydroxydecanoate.

Key words: cerebral ischemia • decanoic acids • diazoxide • hippocampus • ischemic preconditioning • potassium channels • sulfonylurea receptors • mice

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